Project Summary The majority of cases of Parkinson's disease (PD) are not caused by an inherited monogenic mutation and etiology involves a combination of genetic and environmental factors. Epidemiological studies indication that pesticide exposure, particularly to organochlorine pesticides such as dieldrin, increases risk of developing PD. The defining pathological hallmark of PD is the formation of ?-synuclein (?-syn) containing cytoplasmic inclusions known as Lewy bodies. We hypothesize that environmental exposures modify risk of PD by modifying neuronal vulnerability to ?-Syn-induced neurotoxicity. In this proposal, we will test if developmental exposure to dieldrin alters susceptibility of neurons to ?-syn-induced neurotoxicity. Dieldrin is an organochlorine pesticide linked to PD by epidemiological, mechanistic and post-mortem studies. Mice exposed to dieldrin during development show 1) changes in dopamine neurochemistry that persist into adulthood and 2) increased susceptibility to adult exposure to the dopaminergic toxicant MPTP. However, the relevance of MPTP to PD pathophysiology has been questioned. Instead, the ?-Syn pre-formed fibril (PFF) model has emerged as a more accurate representation of the ?-Syn pathology and toxicity central to PD pathogenesis. The PFF model offers a unique opportunity to connect exposures to increased neuronal vulnerability to synucleinopathy. The experiments proposed here will specifically test if developmental exposure to dieldrin increases 1) the propensity of ?-Syn to aggregate and 2) the degree of neurodegeneration caused by PFF-induced ?- syn inclusions. Completion of these aims will further the goals of NIEHS to identify and understand shared mechanisms or common biological pathways underlying complex disease. The experiments proposed here will help to establish a biological mechanism linking a developmental exposure to late life disease. When combined with our currently funded studies on epigenetic changes induced by developmental dieldrin exposure, the details of this mechanism will begin to emerge in greater detail and lay the groundwork for future mechanistic studies. In addition, the experimental design employed here will establish a paradigm to further the goals of NIEHS to understand how combined exposures affect disease pathogenesis and individual susceptibility. The paradigm will allow us to test a wide variety of exposures, as well as combinations of exposures, and to explore the mechanisms by which PD-related exposures alter neuronal vulnerability to synucleinopathy in Parkinson's disease.